Anti-inflammatory compound having inhibitory activity against multiple tyrosine kinases and pharmaceutical composition containing same

Abstract

The present invention is for the anti-inflammatory compounds that have an inhibitory activity against protein tyrosine kinases and their pharmaceutical composition(s) containing the compound as the active ingredient. Since the compounds of the present invention can inhibit multiple protein kinases associated with inflammatory diseases and immune disorders, they are useful for their prevention or treatment.

The invention claimed is: 
     
       1. A compound of the following chemical formula 1, or pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         wherein,
 X 1  is N or CH; 
 R 1  is —OH or —OCH 3 ; 
 Y is C 6-10  aryl substituted with R 2 , or C 5-10  heteroaryl substituted with R 2  or N-methylpiperazinyl; 
 R 2  is —(CH 2 ) n —R 3 , —(CH 2 ) n —C(O)—R 3 , or —O(CH 2 ) n —R 3 ; 
 R 3  is —H, —CN, halogen, C 1-3  alkyl, C 1-3  alkoxy, phenyl, pyridinyl, amino, C 1-3  alkyl amino, di C 1-3  alkyl amino, hydroxyl C 1-3  alkyl amino, carboxy C 1-3  alkyl amino, C 3-6  cycloalkyl C 1-3  alkylamino, pyrolidinyl, hydroxyl pyrolidinyl, hydroxyl C 1-3  alkylpyrolidinyl, carboxypyrolidinyl, piperidinyl, C 1-3  alkylpiperidinyl, di C 1-3  alkyl piperidinyl, piperazinyl, C 1-3  alkylpiperazinyl, C 1-4  alkoxycarbonylpiperazinyl, or morpholinyl; and 
 n is an integer selected from 0 to 3, and 
 
         wherein the compound of the chemical formula 1 is any one selected from the group consisting of— 
         3(6-(phenylthieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         4-(4-(3-methoxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzonitrile, 
         4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzonitrile, 
         4-(4-(3-methoxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenol, 
         3-[6-(4-methoxyphenyl)-thieno[3,2-d]pyrimidine-4-nylamino]-phenol, 
         N-(3-methoxyphenyl)-6-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-d]pyrimidine-4-amine, 
         3-(6-(4-chlorophenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         N-(3-methoxyphenyl)-6-(4-phenethoxyphenyl)thieno[3,2-d]pyrimidine-4-amine, 
         N-(3-methoxyphenyl)-6-(4-(2-(pyridine-2-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidine-4-amine, 
         (6-furan-2-yl-thieno[3,2-d]pyrimidine-4-yl)-(3-methoxyphenol)-amine, 
         (6-furan-3-yl-thieno[3,2-d]pyrimidine-4-yl)-(3-methoxyphenol)-amine, 
         N-(3-methoxyphenyl)-6-(4-(2-(pyrolidine-1-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidine-4-amine, 
         N-(3-methoxyphenyl)-6-(thiophene-2-yl)thieno[3,2-d]pyrimidine-4-amine, 
         (3-methoxyphenyl)-(6-thiophene-3-yl-thieno[3,2-d]pyrimidine-4-yl)-amine, 
         N-(3-methoxyphenyl)-6-(4-(2-(piperazine-1-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidine-4-amine, 
         (3-methoxyphenyl)-(6-thiophene-2-yl-thieno[3,2-d]pyrimidine-4-yl)-amine, 
         3-(6-thiophene-3-yl-thieno[3,2-d]pyrimidine-4-ylamino)-phenol, 
         3-((6-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-(piperazine-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-(pyrolidine-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-(piperidine-ylmethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-((4-methylpiperazine-1-yl-methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-((diethylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-((cyclopropylmethylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-((isobutylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-((ethylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-(2-(pyrolidine-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-(2-(piperidine-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-((6-(4-(2-(4-methylpiperazine-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-(2-morpholinoethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenyl)-1-(4-methylpiperazine-1-yl)ethanone, 
         2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenyl)-1-(pyrolidine-1-yl)ethanone, 
         N,N-diethyl-2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenyl)acetamide, 
         3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzoic acid, 
         (4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenyl)(4-methylpiperazine-1-yl)methanone, 
         (3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenyl(pyrolidine-1-yl)methanone, 
         N,N-diethyl-3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzamide, 
         (3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)phenyl(4-methylpiperazine-1-yl)methanone, 
         methyl 1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzyl)pyrolidine-2-carboxylate, 
         3-(6-(4-((2-(hydroxymethyl)pyrolidine-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-((4-methylpiperidine-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-(((2R,6S)-2,6-dimethylpiperidine-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-(piperidine-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-((4-methylpiperazine-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-(pyrolidine-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-((diethylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-(piperazine-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-((ethylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzyl)pyrolidine-2-carboxamide HCl salt, 
         1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzyl)pyrolidine-2-carboxylic acid HCl salt, 
         3-(6-(4((2-hydroxyethylamino)methyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         methyl 2-(3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzamido)propanoate, 
         1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzyl)pyrolidine-3-ol HCl salt, 
         3-(6-(4-(ethoxymethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)-N-(1-hydroxyprophane-2-yl)benzamide, 
         2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidine-6-yl)benzamido)prophane acid, 
         3-(6-(3-(2-(pyrolidine-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(3-(2-(piperazine-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(2-(4-(pyrolidine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(6-(4-morpholinophenyl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(4-((4-methylpiperazine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(6-(5-(pyrolidine-1-ylmethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-(pyrolidine-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5((4-methylpiperazine-1-yl)methyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-(piperidine-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-(morpholinomethyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-(piperazine-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-((ethylamino)methyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-((4-methylpiperazine-1-yl)methyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-(piperidine-1-ylmethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-(piperazine-1-ylmethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(5-((ethylamino)methyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(2-(4-(piperidine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(4-(piperazine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(4-((ethylamino)methyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(4-methylpiperazine-1-yl)thiazolo[4,5-d]pyrimidine-7-ylamino)phenol, 
         3-(6-(4-(pyrolidine-1-ylmethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-((4-methylpiperazine-1-yl)methyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-(piperidine-1-ylmethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-(morpholinomethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol trifluoroacetic acid) 
         3-(6-(4-(piperazine-1-ylmethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol trifluoroacetic acid 
         3-(6-(4-((ethylaminomethyl)thiophene-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(2-(3-(pyrolidine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(3-((4-methylpiperazine-1-yl)methyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(3-(piperidine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(3-(piperazine-1-ylmethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(2-(3-((ethylamino)methyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol, 
         3-(6-(4-(pyrolidine-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol, 
         3-(6-(4-((4-methylpiperazine-1-yl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol trifluoroacetic acid or 
         3-(6-(4-(piperidine-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidine-4-ylamino)phenol. 
       
     
     
       2. The compound according to  claim 1 , wherein the compound is 3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridine-7-ylamino)phenol. 
     
     
       3. The compound according to  claim 1 , wherein the pharmaceutically acceptable salt is inorganic salt, organic carboxylic acid salt or sulfonic acid salt. 
     
     
       4. The compound according to  claim 3 , wherein the inorganic salt is HCl salt and the organic carboxylic acid salt is trifluoroacetic acid salt. 
     
     
       5. A pharmaceutical composition for treating scar formation in wound healing process, asthma or atopic dermatitis, comprising the compound according to  claim 1  as an active ingredient. 
     
     
       6. The pharmaceutical composition according to  claim 5 , wherein the wound is characterized by trauma, burns, pressure ulcers, or one caused by diabetic foot ulcers. 
     
     
       7. The pharmaceutical composition according to  claim 5 , wherein the pharmaceutical composition is administrated at a dose of 0.1 to 500 mg/kg body weight. 
     
     
       8. The pharmaceutical composition according to  claim 5 , wherein the pharmaceutical composition is for dermal administration. 
     
     
       9. The pharmaceutical composition according to  claim 5 , wherein the pharmaceutical composition is formulated as an ointment, cream or patch type. 
     
     
       10. A method for treating scar formation in wound healing process, asthma or atopic dermatitis, comprising the step of administering into a patient a therapeutically effective amount of the compound according to  claim 1 , or pharmaceutically acceptable salts thereof.